The long term goals of this project are to derive a more complete understanding of the physiology of natural killer (NK) cells in human intestines and to define differences that exist in intestinal tissue of Inflammatory Bowel Disease (IBD). From previous work we have established a hypothesis for immune abnormalities in IBD. We hypothesize that due to the over regulation of lymphoblastoid B cells (B cells which are essential for successful antibody responses to exogenous antigens) by NK cells, humoral hypo responsiveness results. To test whether these abnormalities which have been demonstrated in peripheral blood cells from (IBD) patients might be operant in gut associated lymphoid populations, we tested for the presence of LB cells in gut tissues. We have preliminary results suggesting existance of IgG and IgA LB cells in normal intestines and decreased activity of these in IBD. These results suggest that over activity of such NK cells in IBD intestines may be responsible for this lowered LB activity. Specific aims of this continuation grant are designed to evaluate the validity of this hypothesis at the gut level by testing for the presence and changes in activity of these NK subsets in normal and IBD isolated mesenteric nodes and intestinal lymphoid populations. Specifically we plan to (1) define the phenotype of subsets of NK K562 cells active in IBD gut mesenteric nodes using monoclonal antibodies. (2) to define the suppressor cell of NK function present in normal intestinal tissue and further test activity in IBD specimens; (3) to study the existence, type, and level of activity of NK cells active against LB cells in normal and IBD intestines and mesenteric nodes by a) using PBL associated LB cells as indicator targets, b) defining IgG and IgA and LB activity in normal intestines, c) defining activity of PBL NK subsets in suppressing the functions of LB cells from normal and IBD intestines and d) testing for activity of gut NK LB cells on separated IgG and IgA LB cells from normal IBD intestines. These studies will allow us to test a model at the intestinal level which may help explain a pertinent underlying immune regulatory abnormality existing in IBD. Moreover, they will greatly extend our knowledge of the basic physiology of NK mucosal cells and the mechanisms involved in the terminal regulation in mucosal antibody response in humans.